Prophylactic Azithromycin Therapy After Lung Transplantation: Post hoc Analysis of a Randomized Controlled Trial

Am J Transplant. 2016 Jan;16(1):254-61 doi: 10.1111/ajt.13417.
Abstract

Prophylactic azithromycin treatment has been demonstrated to improve freedom from bronchiolitis obliterans syndrome (BOS) 2 years after lung transplantation (LTx). In the current study, we re-evaluated the long-term effects of this prophylactic approach in view of the updated classification system for chronic lung allograft dysfunction (CLAD). A retrospective, intention-to-treat analysis of a randomized controlled trial comparing prophylactic treatment with placebo (n = 43) versus azithromycin (n = 40) after LTx was performed. Graft dysfunction (CLAD), graft loss (retransplantation, mortality), evolution of pulmonary function and functional exercise capacity were analyzed 7 years after inclusion of the last study subject. Following LTx, 22/43 (51%) patients of the placebo group and 11/40 (28%) patients of the azithromycin group ever developed CLAD (p = 0.043). CLAD-free survival was significantly longer in the azithromycin group (p = 0.024). No difference was present in proportion of obstructive versus restrictive CLAD between both groups. Graft loss was similar in both groups: 23/43 (53%) versus 16/40 (40%) patients (p = 0.27). Long-term pulmonary function and functional exercise capacity were significantly better in the azithromycin group (p < 0.05). Prophylactic azithromycin therapy reduces long-term CLAD prevalence and improves CLAD-free survival, pulmonary function, and functional exercise capacity after LTx.

CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion: This manuscript reports a long-term, retrospective analysis of an RCT comparing prophylactic azithromycin to placebo in lung transplant recipients. Azithromycin has anti-inflammatory and immunomodulatory properties and was shown in an earlier analysis to improve freedom from bronchiolitis obliterans early after lung transplant. Since then, the classification of chronic lung allograft dysfunction (CLAD) has been revised and the authors here provide a retrospective analysis of the 7-year follow-up of the patients in the trial, using the new CLAD classification. The analysis demonstrates a significant reduction in the incidence of CLAD (and improved CLAD free survival time) with prophylactic azithromycin. Long-term pulmonary function and functional exercise capacity were also significantly better in the treatment arm. Data regarding tacrolimus levels are missing from the manuscript – there are some case reports of interaction between azithromycin and tacrolimus, and erratic tacrolimus levels have been shown to be predictive for development of CLAD. This is a relatively small, retrospective analysis and so should be regarded as exploratory, but nonetheless provides some evidence of a role for prophylactic azithromycin in these patients.
Expert Review
Reviewer: Professor Stuart C. Sweet, Washington University, St. Louis, MO, USA
Conflicts of Interest: No
Clinical Impact Rating 4
Review: The article by Ruttens and colleagues provides additional follow-up details 7 years after enrolment of the final patient from a cohort who participated in a randomized, controlled trial of prophylactic azithromycin (AZI) therapy in lung transplant recipients. Using an intention to treat analysis, the original study population was analysed using the updated allograft dysfunction (CLAD) classification. The key findings of the study included the observation that CLAD-free survival was longer in the azithromycin group, pulmonary function and exercise capacity were better in the azithromycin group (these differences were felt to have developed in the first 2 years of follow-up) and no overall difference in graft survival (felt to be related to the use of open label AZI in both the treatment and placebo groups). No AZI significant side effects were noted. Although this is a single centre study limited by retrospective design of the longer term follow-up, it suggests that centres should consider whether the potential benefit of using AZI prophylaxis in lung transplant recipients may outweigh the potential risks. These findings will benefit from confirmation in a multicentre study, ideally with inclusion of mechanistic analyses.
Methodological quality
Jadad score 5
Allocation concealment YES
Data analysis INTENTION TO TREAT
Score based on Vos R, et al. A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation. Eur Respir J 2011
Study Details
Aims: To evaluate the long-term effects of prophylactic azithromycin therapy post lung transplantation in view of the recently updated classification system for chronic lung allograft dysfunction (CLAD).
Interventions: Participants were randomized to receive either azithromycin (250mg) three times per week, or placebo.
Participants: 83 single-lung, bilateral lung or heart–lung transplant recipients >18 years of age, previously included in a randomized controlled trial of azithromycin versus placebo*
Outcomes: Outcomes measured were CLAD, graft loss, pulmonary function and functional exercise capacity.
Follow Up: 7 years
Metadata
Funding: Non-industry funding
Publication type: Randomized Controlled Trial, Randomised Controlled Trial
Trial registration: ClinicalTrials.gov - NCT01009619
Organ: Lung
Language: English
Author email: robin.vos@uzleuven.be
MeSH terms: Anti-Bacterial Agents; Antibiotic Prophylaxis; Azithromycin; Bacteremia; Bronchiolitis Obliterans; Cohort Studies; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Graft Rejection; Graft Survival; Humans; Lung Transplantation; Male; Postoperative Complications; Prognosis; Risk Factors; Syndrome; Transplantation, Homologous; 0 (Anti-Bacterial Agents); 83905-01-5 (Azithromycin)